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Tuesday, June 23, 2015

When it feels that everything has been said, it may be time to be silent for a while.

This point has come for me and the RNAi Therapeutics blog and I look forward to take part in the conversation with renewed energy and ideas. Until then, you can follow the 'light' version of this blog on Twitter @RNAiAnalyst.

Thursday, June 11, 2015

The fairy-tale story of the splice modulation for spinal muscular atrophy (SMA) continues. This
morning, Isis Pharmaceuticals provided an update on the phase II study of
ISIS-SMNRx in type I SMA infants. The data built on already highly promising data as of last September, showing that a doubling (~9 to ~18 months)
of the median ‘event-free survival’ compared to the Natural History has now
been reached with numbers still increasing as more than half the infants remain event-free.

Only one out
of 12 infants still on study suffered an event (permanent ventilation) over the
last 9 months. This one in 108 month
event rate compares to 6 events in ~200 months in the prior phase of the
study, suggesting that if babies can be diagnosed and treated early enough so
that they are covered during a critical period of development (e.g. maturation
of the neuromuscular synapse) chances are that they will enjoy a very
significant treatment benefit from ISIS-SMNRx.

This is thus
consistent with the biomarker data showing that ISIS-SMNRx increases the
missing functional full-length SMN protein by 2-3 times essentially turning a
type I SMA infant (usually 2 copies of SMN2) with an 80% chance of dying or
going on permanent ventilation by 18 months into a much milder form of the
disease where patients have 4 or more copies of SMN2 and have an almost normal
life expectancy (note: those with 3 copies, usually type II SMA, live into
teens/early adulthood).

While as a
parent, I would almost do anything for my child to get access to the drug and I
do understand there to be calls for immediate (à once diagnosed, the window of
treatment opportunity may be quite narrow) regulatory action, the first
consequence of today’s data should be getting SMA on mandatory genetic panels for newborn screening. Only then
will there be maximal benefit once the ongoing blinded phase III study reads
out in late 2016/early 2017.

Wednesday, June 10, 2015

How times have changed. Four years ago, Alnylam found itself on the
receiving end of a trade secret lawsuit regarding the delivery technology du jour,
SNALP LNP then, in which it ended up paying near-bankrupt Tekmira ~$70M to settle the
allegations. As I opined back then, Alnylam seemingly used almost any means to get access to the know-how to make
SNALP LNP delivery work in primates in an effort to rid itself of the reliance
on Tekmira, the inventors.

An interesting aside
of this is that it appears, contrary to representations by Alnylam, that the
GalNAc-ESC technology were invented at Merck, not in-house at Alnylam.

The Complaint makes it clear that Alnylam feels threatened
by the technologically very direct competition.
In a way, Dicerna’s new strategy was to become Alnylam's clone. What could be worse, given the differences in the
RNAi trigger lengths (~19bp Tuschl-type siRNAs by Alnylam; 25/27 and longer Dicer-substrate
versions by Dicerna) and the apparent importance of stability/degradation in
GalNAc technology, there is the distinct possibility that Dicerna’s version,
everything else being equal, would outperform (or underperform) Alnylam’s.

In light of recent apparently rapid progress at Dicerna on
GalNAc technology and the timing of events, the idea that Dicerna may have
benefited from the GalNAc know-how of ex-Merck scientists does not seem
far-fetched.

It is unclear to me,
however, whether you can expect expert oligonucleotide chemists to suddenly
forget everything about their former job.

Alnylam obviously takes care of that problem by enforcing
harsh non-compete and pay-for-silence practices against their former employees,
meaning that if you are an RNAi scientist that job at Alnylam will be your last
RNAi job in the industry, period.

Looking forward, I predict that the outcome of the case will hinge less on
the physical documents that were alleged to have been ‘misappropriated’, but on
whether or not the ex-Merck scientists could have re-invented GalNAc-ESC based
on their skills and publicly available information (including from Alnylam) at
the time. If so, then Alnylam only has
Merck to blame that it does not force their employees to leave their profession
when they lay them off.

Thursday, June 4, 2015

As you will probably know already, Regulus Therapeutics surprised us this
week with the sudden departures of both their CEO and CSO. These two individuals also happened to be the
insiders selling major positions in the stock earlier this year just days ahead
of critical data to be released on their lead clinical candidate, RG-101 for
the treatment of HCV ('Reading the tea leaves on Regulus insider sales').

While this would be a good reason for what looks like a sacking of the company’s two key executives (especially since
the exodus came as a pair), for investors the all-important question is whether
it is also related to bad news that we do not know about yet. Most importantly, does this also have anything to do
with the failure to report the viral resistance analysis which had been promised
to us for the EASL meeting in April?

It is this analysis that will determine whether the miR-122
inhibitor can facilitate 4-week treatment regimens which must be the goal for
this asset. This is because RG-101 is
the only serious long-acting agent out there in the HCV drug development arena
and 4 weeks of oral, short-acting antivirals do not seem capable of getting rid
of the virus.

If there was no resistance to RG-101, based on the available
data RG-101 given on week 4 would add ~6 weeks to deep viral suppression to
the treatment regimen, in a way resembling a 10-week oral regimen which have much higher
odds of viral clearance.
If viral resistance (and not waning drug levels as I am assuming) played a role in the rebounds
seen in the single-dose study, then this would not necessarily be the
case. I say ‘not necessarily’ because
even then, the risk of developing viral resistance to RG-101 should be much lower when given in
combination with other agents as is the plan.

Take-home: I remain cautious (but not short any more)
prepared to take advantage of another bout of panic selling that could come
with the release of the resistance analysis.
The quality of the new leadership to lead the exciting microRNA platform
will also indicate whether Regulus can finally live up to its original promise.
Long-term, whether precipitated by the insider sales or not, the changes should be good as morale at the company from what I can tell had been low.

PS: in more positive news, Regulus Therapeutics today reported
that a first-in-man study with their second most advanced microRNA Therapeutic,
RG-012 for the kidney-related orphan disease Alport Syndrome, has begun dosing.

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